Association of Immune-Related Adverse Event Management With Survival in Patients With Advanced Melanoma

Abstract

ImportanceManagement of checkpoint inhibitor–induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of anti–tumor necrosis factor on checkpoint-inhibitor efficacy.ObjectiveTo determine the association of toxic effect management with progression-free survival (PFS), overall survival (OS), and melanoma-specific survival (MSS) in patients with advanced melanoma treated with first-line ipilimumab-nivolumab combination therapy.Design, Setting, and ParticipantsThis population-based, multicenter cohort study included patients with advanced melanoma experiencing grade 3 and higher irAEs after treatment with first-line ipilimumab and nivolumab between 2015 and 2021. Data were collected from the Dutch Melanoma Treatment Registry. Median follow-up was 23.6 months.Main Outcomes and MeasuresThe PFS, OS, and MSS were analyzed according to toxic effect management regimen. Cox proportional hazard regression was used to assess factors associated with PFS and OS.ResultsOf 771 patients treated with ipilimumab and nivolumab, 350 patients (median [IQR] age, 60.0 [51.0-68.0] years; 206 [58.9%] male) were treated with immunosuppression for severe irAEs. Of these patients, 235 received steroids alone, and 115 received steroids with second-line immunosuppressants. Colitis and hepatitis were the most frequently reported types of toxic effects. Except for type of toxic effect, no statistically significant differences existed at baseline. Median PFS was statistically significantly longer for patients treated with steroids alone compared with patients treated with steroids plus second-line immunosuppressants (11.3 [95% CI, 9.6-19.6] months vs 5.4 [95% CI, 4.5-12.4] months; P = .01). Median OS was also statistically significantly longer for the group receiving steroids alone compared with those receiving steroids plus second-line immunosuppressants (46.1 months [95% CI, 39.0 months-not reached (NR)] vs 22.5 months [95% CI, 36.5 months-NR]; P = .04). Median MSS was also better in the group receiving steroids alone compared with the group receiving steroids plus second-line immunosuppressants (NR [95% CI, 46.1 months-NR] vs 28.8 months [95% CI, 20.5 months-NR]; P = .006). After adjustment for potential confounders, patients treated with steroids plus second-line immunosuppressants showed a trend toward a higher risk of progression (adjusted hazard ratio, 1.40 [95% CI, 1.00-1.97]; P = .05) and had a higher risk of death (adjusted hazard ratio, 1.54 [95% CI, 1.03-2.30]; P = .04) compared with those receiving steroids alone.Conclusions and RelevanceIn this cohort study, second-line immunosuppression for irAEs was associated with impaired PFS, OS, and MSS in patients with advanced melanoma treated with first-line ipilimumab and nivolumab. These findings stress the importance of assessing the effects of differential irAE management strategies, not only in patients with melanoma but also tumor types.

Toxicity-specific peripheral blood T and B cell dynamics in anti-PD-1 and combined immune checkpoint inhibition

“…This is, for instance, illustrated by the more acute onset, the possibility of complete irAE reversibility with adequate therapy and shorter time-to-response of biologicals [5]. Together with the concern that targeted immunosuppression may thwart antitumor immunity [6, 7], these observations underscore that evidence-based irAE treatment requires more profound biological understanding of specific mechanisms underlying ICI-induced toxicity.…”

Immune-related adverse events in checkpoint blockade: Observations from human tissue and therapeutic considerations

“…On the other hand, whilst the need for irAE treatment with immunosuppression within two months of CPI initiation has been suggested to be deleterious for cancer outcome ( 92 ), the confounding impact of premature CPI cessation in this context also remains unclear. The same important caveat applies to data suggesting escalation of immunosuppression, to include targeted interventions including biologic drugs on top of glucocorticoids ( 93 ). It should also be remembered that high-dose glucocorticoid use is itself associated with considerable morbidity ( 94 – 96 ).…”

Steroid Dose and Duration, Immortal Time Bias, and Survival After High-grade Immune-Related Adverse Events—Reply

“…In Reply We would like to thank Reid et al for their valuable comments on our cohort study in which we demonstrated an association between dual immune checkpoint inhibitors (ICIs) and impaired survival in patients with grade 3 or higher immune-related adverse events (irAEs) who received second-line immunosuppressants compared with those who only received corticosteroids . Reid and colleagues raise important questions concerning possible biases in our analyses with respect to steroid use and the potential for immortal time bias.…”